Respiratory dysfunction presents a major challenge to both the cardiovascular and respiratory systems. Hypoxia and hypercapnia slow respiration and evoke a pronounced bradycardia mediated by increases in parasympathetic cardiac activity. These cardiorespiratory responses to hypoxia/hypercapnia normally serve to prolong survival by reducing the metabolic demands of cardiac and respiratory muscles. However, exaggerated responses to hypoxia and/or hypercapnia may be life threatening and have been implicated in cardiovascular diseases, including Sudden Infant Death Syndrome (SIDS). Fetal nicotine exposure is among the highest risk factors for SIDS and infants that succumb to SIDS have a severe centrally mediated slowing of the heart, which accompanies single or intermittent periods of hypoxia/hypercapnia. While it is well accepted activation of chemosensitive neurons and pathways within the brainstem alter respiratory activity and increase parasympathetic cardiac efferent activity, there is a scarcity of information concerning the mechanisms responsible for this excitation of cardiac vagal neurons. This competitive renewal proposal directly addresses this critical and clinically important cardiorespiratory interaction. We will test the hypotheses that single and/or episodic periods of central hypoxia, hypercapnia and combined hypoxia/hypercapnia recruit a respiratory related excitatory pathway to cardiac vagal neurons. In addition we will test the hypothesis that prenatal exposure to nicotine exaggerates this excitation, and this facilitation is mediated by activation of nicotinic receptors. Our third goal is to test the hypothesis that generation of oxygen free radicals are involved in the recruitment of the excitatory pathway in both unexposed and prenatal nicotine exposed animals, to localize the production of oxygen free radicals in the medulla, and test if stimulation of the site(s) of oxygen free radical production activates monosynaptic glutamatergic pathways to cardiac vagal neurons. Each of these hypotheses is supported by our Preliminary Data. This work will not only address hypotheses fundamental to understanding the basis and mechanisms of responses in cardiac vagal neurons in response to hypoxia and hypercapnia that originate in the medulla, but will also suggest which receptors and processes could be altered by fetal exposure to nicotine that increases the risk of cardiorespiratory diseases such as SIDS.